Abstract 3181: IL-23 knockdown profoundly suppresses intestinal tumorigenesis in APCmin mice
Authors: Venkateshwar Madka, Srikanth Chiliveru, Gopal Pathuri, Janani Panneerselvam, Rajani Rai, Nicole C. Stratton, Nandini B. Kumar, Yuting Zhang, Chinthalapally V Rao
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) is the 3rd most common cancer in the US with an estimated 149,500 new cases and 52,980 deaths in 2021. Studies show that Western-style diet-induced obesity promote CRC by modulating gut inflammatory mediators. We found significant increase in IL-23 levels (p&amp;lt;0.0001) in obese human subjects' plasma (n=15/arm; BMI&amp;gt;30) and its. over expression in colonic tumors (CT) from human and rodent models that highly correlated with, the TCGA gene expression &amp; disease-free survival data. These findings suggested IL-23 as a possible important link between obesity and colon tumorigenesis. The present study was designed to understand the role of IL-23 in colorectal carcinogenesis by using genetic knockout (KO) approach. For this study, Apcmin/+ and IL-23 KO mice were crossbred to generate Apcmin/+ mice with IL-23 in heterozygous or KO conditions. To determine the effect of IL-23 on intestinal tumorigenesis, six-week-old Apcmin/+ mice (N≥15/gender) were grouped by IL-23 genotype i.e., normal (+/+), heterozygous (+/-) and KO (-/-) conditions, then maintained under standard conditions. At 20 weeks of age, all mice were euthanized and intestines were evaluated and compared for tumors incidence and multiplicity. Genetic ablation of IL-23 led to significant suppression of large and small intestinal tumors of APCmin/+ mice in both genders. CT multiplicity of male and female IL-23+/+ Apcmin/+ mice were 1.35±0.16 (Mean±SEM) and 0.61±0.13, respectively. Male and female IL-23+/- Apcmin/+ mice had 77% (0.31+0.15; p&amp;lt;0.0001) and 90% (0.06+0.09; p&amp;lt;0.002) inhibition of CTs, respectively. Interestingly, IL-23 KO led to further suppression in male mice (96% inhibition in male; 0.05+0.05; p&amp;lt;0.0001 and 90% in females; 0.06+0.06; p&amp;lt;0.0001). While IL-23+/+ Apcmin/+ mice was 91% and 52% CT incidence in the male and female mice, respectively. CT incidence was suppressed by 72% (male, p&amp;lt;0.0001) &amp; 88% (female, p&amp;lt;0.005) in the IL-23+/- mice, with further suppression to 95% (male, p&amp;lt;0.0001) &amp; 89% (female, p&amp;lt;0.0025) inhibition in IL-23 KO mice. The strong suppressive effect of IL-23 knockdown was also observed on the small intestinal polyps (SIP) multiplicity. There was a 54% (12.56±1.64; p&amp;lt;0.0001) and 58% (11.45±1.03; p&amp;lt;0.0001) reduction in SIP number in IL23+/- and IL23-/- male Apcmin/+ mice, compared to the IL-23+/+ control mice (27.48±2.38). In female, 55-59% (13.88±1.05 and 12.73±2.03; p&amp;lt;0.0001) less SIP were observed with IL-23 ablation compared to control (30.90±2.54). Apcmin/+ with IL-23 KO showed significant reduction in circulating proinflammatory cytokine and chemokines (Ex: IL-1, IL-10, IL-17, IL-23, CCL-2, CCL-3, CCL-5, TNFa, IFNg) levels compared to IL-23 WT mice. These results clearly demonstrate the colon tumor-promoting role of IL-23 and strengthens our hypothesis to explore this target for CRC prevention in high-risk obese individuals. (Supported in part by P30 CA225520 and Kerley-Cade Endowed Chair) Citation Format: Venkateshwar Madka, Srikanth Chiliveru, Gopal Pathuri, Janani Panneerselvam, Rajani Rai, Nicole C. Stratton, Nandini B. Kumar, Yuting Zhang, Chinthalapally V Rao. IL-23 knockdown profoundly suppresses intestinal tumorigenesis in APCmin mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3181.